Biodegradable polymer microsphere compositions for parenteral administration

ABSTRACT

Novel microsphere compositions for use in parenteral formulations are provided. The microspheres comprise a biodegradable polymer of a molecular weight greater than 10,000 daltons, an active therapeutic agent, and a cellulose-derived material such as ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose, or sodium carboxymethyl cellulose. The microsphere compositions decreased deviation in mean microsphere diameter, improved drug entrapment, and improved microsphere stability.

BACKGROUND

Cellulose ethers and esters such as ethyl cellulose are water insolublebinders used widely in oral drug formulation (such as tablets, pills,capsules) for their ability to intercalate material matrices and providephysical integrity and humidity resistance. Ethyl cellulose is amaterial that is generally recognized as safe (GRAS) for oral drugformulation. Ethyl cellulose is not, however, used in parenteral drugformulation.

Biodegradable polymers such as polylactides, polylactide-co-glycolidesand polyanhydrides have been used in parenteral drug formulations. Theyhave also been used in some wound healing powders applied topically.

SUMMARY

The present disclosure outlines the benefits of including cellulosederivatives such as ethyl cellulose in combination with biodegradablepolymers that are used exclusively in parenteral drug formulation.

The present disclosure relates to novel microsphere compositions forparenteral administrations. The compositions comprise a plurality ofmicrospheres, wherein each microsphere comprises a homogenous mixture ofa biodegradable polymer, an active therapeutic agent, and acellulose-derived material, and wherein the biodegradable polymer has amolecular weight of greater than 10,000 Daltons.

Embodiments include:

The composition wherein the percentage of biodegradable polymer is fromabout 50% to about 95% w/w of each microsphere.

The composition wherein the biodegradable polymer comprises abulk-eroding polymer; such as wherein the biodegradable polymercomprises a polyester polymer comprising lactide, glycolide, or acombination thereof as a co-block polymer; wherein the biodegradablepolymer comprises a polyester polymer comprising a co-block polymerselected from the group consisting of poly(D,L-lactide-co-glycolide) andpoly(L-lactide-co-glycolide); the composition wherein the co-blockpolymer is poly(D,L-lactide-co-glycolide); preferably wherein thepercentage of lactide is from about 65% to about 85% w/w of the co-blockpolymer and wherein the percentage of glycolide is from about 15% toabout 35% w/w of the co-block polymer; the composition wherein theco-block polymer is poly(L-lactide-co-glycolide); preferably wherein thepercentage of lactide is from about 65% to about 85% w/w of the co-blockpolymer and wherein the percentage of glycolide is from about 15% toabout 35% w/w of the co-block polymer; and/or the composition whereinthe polyester polymer comprises poly(D,L-lactide-co-glycolide) andpoly(D,L-lactide).

The composition wherein the biodegradable polymer comprises asurface-eroding polymer; such as wherein the biodegradable polymercomprises a polyanhydride polymer; including wherein the polyanhydridepolymer comprises 1,ω-bis(carboxy)(C₂-C₁₀)alkane units,1,ω-bis(carboxyphenoxy)(C₂-C₁₀)alkane units, or combinations thereof;and/or the composition wherein the polyanhydride polymer comprises acopolymer of sebacic anhydride and 1,3-bis(p-carboxyphenoxy)propane,1,6-bis-(p-carboxy-phenoxy)hexane, or1,8-bis(carboxyphenoxy)-3,6-dioxaoctane, or combinations thereof.

The composition of any of the preceding embodiments wherein thepercentage of cellulose-derived material is from about 0.5% to about 6%w/w of each microsphere; the composition wherein the cellulose-derivedmaterial comprises ethyl cellulose, carboxymethyl cellulose,hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose orcombinations thereof; notably wherein the cellulose-derived materialcomprises ethyl cellulose.

The composition of any of the preceding embodiments wherein thecellulose-derived material (CDM) comprises a viscosity fraction of about0.1% to about 5%; wherein the viscosity fraction is calculated accordingto the equation

vf_CDM=η_inh_CDM*(f_CDM)/[η_inh_CDM*(f_CDM)+η_inh_Pol*(f_Pol)]*100

wherein vf_CDM=the viscosity fraction vf_CDM in the polymer matrix;η_inh_CDM=the inherent viscosity of the CDM; η_inh_Pol=the inherentviscosity of the polymer, f_CDM=the fraction vf_CDM in the polymermatrix; and f_Pol=the fraction of polymer in the polymer matrix; such aswherein the CDM comprises ethyl cellulose and comprises a viscosityfraction of about 0.1% to about 5%; about 0.5% to about 3.5%; about 0.2%to about 2%; about 0.3% to about 1%; or about 0.5% to about 2%.

The composition of any of the preceding embodiments wherein thepercentage of active therapeutic agent is from about 10% to about 40%w/w of each microsphere; including the composition wherein the activetherapeutic agent is an integrase inhibitor; the composition wherein theactive therapeutic agent is an antiparasitic; the composition whereinthe active therapeutic agent is a steroid hormone; the compositionwherein the active therapeutic agent is a somatostatin analogue; thecomposition wherein the active therapeutic agent is a peptide; and/orthe composition wherein the active therapeutic agent is an organiccompound having a molecular weight of less than 1000 daltons.

The composition of any of the preceding embodiments wherein theplurality of microspheres are suspended in an aqueous carrier.

The composition of any of the preceding embodiments wherein theplurality of microspheres are suspended in a non-aqueous carrier.

The composition of any of the preceding embodiments further comprising agel, wherein the plurality of microspheres are dispersed in the gel.

The composition of any of the preceding embodiments wherein at least 90%of the plurality of microspheres have particle diameters from about 40μm to about 70 μm; wherein at least 90% of the plurality of microsphereshave particle diameters from about 45 μm to about 65 μm; wherein atleast 90% of the plurality of microspheres have particle diameters fromabout 50 μm to about 60 μm; wherein at least 90% of the plurality ofmicrospheres have particle diameters from about 50 μm to about 70 μm;wherein at least 90% of the plurality of microspheres have particlediameters from about 40 μm to about 55 μm; wherein at least 90% of theplurality of microspheres have particle diameters from about 60 μm toabout 100 μm; wherein at least 90% of the plurality of microspheres haveparticle diameters from about 65 μm to about 95 μm; wherein at least 90%of the plurality of microspheres have particle diameters from about 70μm to about 90 μm; wherein at least 90% of the plurality of microsphereshave particle diameters from about 70 μm to about 85 μm; wherein atleast 90% of the plurality of microspheres have particle diameters fromabout 70 μm to about 80 μm; wherein at least 90% of the plurality ofmicrospheres have particle diameters from about 75 μm to about 85 μm.

The composition of any of the preceding embodiments sufficient torelease the active therapeutic agent over a period of at least 100 days;sufficient to release the active therapeutic agent over a period of fromabout 80 days to about 120 days; sufficient to release at least 50% ofthe active therapeutic agent over a period of at least 50 days;sufficient to release at least 60% of the active therapeutic agent overa period of at least 100 days; and/or sufficient to release at least 10%of the active therapeutic agent over a period of at least 50 days.

This invention also provides a pharmaceutical composition including amicrosphere of any of the previous embodiments, and optionally apharmaceutically acceptable carrier and/or excipient.

Embodiments include those wherein the composition is formulated forparenteral administration and further comprises at least one memberselected from the group consisting of an aqueous solution and a buffersolution; wherein the composition further comprises a pharmaceuticalsurfactant and/or wherein the composition further comprises acryoprotectant.

This invention also provides a method for treating a subject having adisease or condition, the method comprising administering a compositionof any of the preceding embodiments to the subject parenterally.

Embodiments include those wherein the subject has a disease or conditionindicating a need for treatment comprising parenteral administration ofan integrase inhibitor, an antiparasitic, a steroid hormone, asomatostatin analogue, a peptide or an organic compound having amolecular weight of less than 1000 daltons.

BRIEF DESCRIPTION OF THE FIGURES

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee. Some specific example embodiments of thedisclosure may be understood by referring, in part, to the followingdescription and the accompanying drawings.

FIGS. 1A to 1E show plots of particle size distribution andphotomicrographs of microspheres prepared in Example 1.

FIG. 2 shows photomicrographs of microspheres prepared in Example 2.

FIG. 3 shows photomicrographs of microspheres prepared in Example 3.

FIG. 4 shows plots of particle size distribution of microspheresprepared in Example 4.

FIGS. 5A to 5F show plots of the cumulative release of the activeingredient from microspheres prepared in Example 5.

FIG. 6 shows a plot of the cumulative release of the active ingredientfrom microspheres prepared in Example 6.

FIG. 7 shows a plot of the cumulative release of the active ingredientfrom microspheres prepared in Example 7.

FIG. 8 shows a plot of the cumulative release of the active ingredientfrom microspheres prepared in Example 8.

FIG. 9 shows a plot of the cumulative release of the active ingredientfrom microspheres prepared in Example 9.

FIG. 10 shows a plot of the cumulative release of the active ingredientfrom microspheres prepared in Example 10.

FIG. 11 shows a plot of the cumulative release of the active ingredientfrom microspheres prepared in Example 11.

FIGS. 12A to 12 C show plots of the cumulative release of the activeingredient from microspheres prepared in Example 12 and stored atelevated temperatures.

FIG. 13 shows photomicrographs of microspheres prepared in Example 13.

DETAILED DESCRIPTION

The term “and/or” means any one of the items, any combination of theitems, or all of the items with which this term is associated. Thesingular forms “a,” “an,” and “the” include plural reference unless thecontext clearly dictates otherwise. Accordingly, the indefinite articles“a” or “an”, as used in the claims, are defined herein to mean one ormore than one of the element that it introduces. Thus, for example, areference to “a compound” includes a plurality of such compounds, sothat a compound X includes a plurality of compounds X. It is furthernoted that the claims may be drafted to exclude any optional element,i.e. an optional element may or may not be present in the claimedembodiment. As such, this statement is intended to serve as antecedentbasis for use of such exclusive terminology as “solely,” “only,” and thelike in connection with the recitation of claim elements, or use of a“negative” limitation.

Whenever a numerical range with a lower limit and an upper limit isdisclosed, any number and any included range falling within the range isspecifically disclosed. In particular, every range of values (of theform, “from about a to about b,” or, equivalently, “from approximately ato b,” or, equivalently, “from approximately a-b”) disclosed herein isto be understood to set forth every number and range encompassed withinthe broader range of values. When ranges are expressed as ranging fromone or more lower limit(s) to one or more upper limit(s), rangescomtemplated may range from any of the enumerated lower limits to any ofthe enumerated upper limits.

While compositions and methods are described in terms of “comprising,”“containing,” or “including” various components or steps, thecompositions and methods can also “consist essentially of” or “consistof” the various components and steps. All numbers and ranges disclosedabove may vary by some amount. Also, the terms in the claims have theirplain, ordinary meaning unless otherwise explicitly and clearly definedherein. If there is any conflict in the usages of a word or term in thisspecification and one or more patent or other documents that may beincorporated herein by reference, the definitions that are consistentwith this specification should be adopted.

As used herein, the term “biodegradable” refers to the ability of acomposition to be broken down, particularly into innocuous products bythe action of living organisms. In particular, it means that the polymercan break down or degrade within the body to non-toxic components afterall bioactive agent or diagnostic agent has been released.“Biocompatible” means materials, or the intermediates, or end productsof materials that are formed by solubilization hydrolysis, or by theaction of biologically formed entities such as enzymes or other productsof the organism, and which cause no adverse effect on the body.

As used herein, the term “hydrophilic” refers to a chemical group havinga tendency to repel non-polar or uncharged chemical groups, e.g.,hexane, and to attract polar or charged chemical groups, e.g., water.“Hydrophilic” also refers to a chemical that tends to dissolve in, mixwith, or be wetted by water. “Hydrophilic” embraces an agent that ispreferably sparingly soluble, soluble, freely soluble, or very soluble,according to USP-NF definitions. As used herein, the term “hydrophobic”refers to a chemical group having a tendency to attract non-polar oruncharged chemical groups, e.g., hexane, and to repel polar or chargedchemical groups, e.g., water. “Hydrophobic” also refers to a chemicalthat tends not to dissolve in, mix with, or be wetted by water. As usedherein, the term “amphiphilic” is used to describe a chemical compoundas possessing both hydrophilic and lipophilic hydrophobic properties.

The terms “drug” or “active agent” or “therapeutic agent” or “bioactiveagent” or “diagnostic agent” shall mean any inorganic or organiccompound or substance having physiologically or pharmacologicallyactivity that acts locally and/or systemically in the body (bioactivity)and is adapted or used for a therapeutic or diagnostic purpose. Any ofthese terms are used herein to refer to a substance that is administeredto a patient for the treatment (e.g., therapeutic agent), prevention(e.g., prophylactic agent), or diagnosis (e.g., diagnostic agent) of adisease or disorder.

As used herein the phrase “therapeutically effective amount” (or moresimply “effective amount”) includes an amount of bioactive agent ordiagnostic agent sufficient to provide a specific therapeutic ordiagnostic response for which the drug is administered to a patient inneed of particular treatment, at a reasonable risk/benefit ratio aswould attend any medical treatment or diagnostic test. The therapeuticeffect could be any therapeutic effect ranging from prevention, symptomamelioration, symptom treatment, to disease termination or cure. Theskilled clinician will recognize that the therapeutically effectiveamount of drug will depend upon the patient, the indication or disease,the treatment being effected, and the particular drug administered.

The terms “treatment” or “treating” means administration of a drug forpurposes including: (i) inhibiting the disease or condition, that is,arresting the development of clinical symptoms; (ii) relieving thedisease or condition, that is, causing the regression of clinicalsymptoms and/or (iii) preventing the disease or condition, that is,causing the clinical symptoms of the disease or condition not todevelop. As used herein, the terms also mean administration of adiagnostic agent useful for detection of a condition in a subject thatis indicative or characteristic of a disease or disorder. As usedherein, the term “prevention” refers to a forestalling, includingtemporary forestalling, of the onset of a disorder. As used herein, theterm “indicative” means to have the characteristics of a certain diseaseor to suggest the presence of status of a certain disease. As usedherein, “administering” and similar terms mean delivering thecomposition to an individual being treated.

“Parenteral” shall mean any route of administration other than thealimentary canal and shall specifically include intramuscular,intraperitoneal, intra-abdominal, subcutaneous, and, to the extentfeasible, intravenous.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition and is generally safe, non-toxic, and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.Examples of “pharmaceutically acceptable liquid carriers” include water,organic solvents, gels, creams and the like. Preferred pharmaceuticallyacceptable aqueous liquids or solutions include phosphate bufferedsaline (PBS), saline, and dextrose solutions.

“Peptide”, “polypeptide”, “oligopeptide,” and “protein” are usedinterchangeably herein when referring to peptide or protein agents andshall not be limited as to any particular molecular weight, peptidesequence or length, field of bioactivity, diagnostic use, or therapeuticuse unless specifically stated. However, preferred proteins and peptideshave molecular weights ranging from about 1 kDa to 500 kDa (e.g., about1, 10, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 kDa or somerange therebetween).

“Small molecule,” as used herein, refers to molecules with a molecularweight of less than about 2000 daltons (g/mol), such as less than about1500 daltons, less than about 1000 daltons, or less than about 600daltons.

The term “polymer” refers to a molecule of one or more repeatingmonomeric residue units covalently bonded together by one or morerepeating chemical functional groups. The term includes all polymericforms such as linear, branched, star, random, block, graft and the like.It includes homopolymers formed from a single monomer, copolymers formedfrom two or more monomers, terpolymers formed from three or morepolymers and other polymers formed from more than three monomers.Differing forms of a polymer may also have more than one repeating,covalently bonded functional group.

The microspheres described herein, wherein the polymers described hereinare combined with a cellulose-derived material and a therapeutic agent,can be used to provide drug delivery systems or devices, orpharmaceutical compositions.

The composition of the invention comprises microspheres comprising (a) abiodegradable polymer such as poly(DL-lactide)poly(DL-lactide-co-glycolide) and/or polyanhydrides, (b)cellulose-derived material; and (c) at least one pharmacologicallyactive sub stance.

In the simplest systems, microspheres are comprised of a polymerconstituent and a drug constituent by dissolving the polymer in anorganic solvent and either co-solubilizing the drug or suspending thedrug in the same phase. Microspheres may be manufactured by formingdroplets of the drug/polymer/organic (discontinuous) phase in anon-solvent (continuous) phase. Droplet formation can be random (such asin emulsion technologies) or highly controlled (such as in precisionparticle fabrication technology). When the microsphere constituentsconsist only of polymer and solvent, droplet formation and shapeuniformity is a function of the solvent, polymer, and continuous phase.When the microsphere constituents also contain a drug, droplet formationand shape uniformity will also depend on the drug and its solubility inthe continuous and discontinuous phases. As drug fraction increases, theability of the droplets to solidify and form uniform spherical shapescan become more difficult if the physicochemical properties of the drugand polymer are very dissimilar, as the case with most drug-polymersystems. When a cellulose-derived material such as a cellulose ether orcellulose ester (e.g. ethyl cellulose) is included with thebiodegradable polymers at specific ranges of viscosity fractions, thepresent disclosure reveals many advantages, such as decreased deviationin mean microsphere diameter, improved drug entrapment, and improvedmicrosphere stability as inferred from dissolution behavior.

Biodegradable Polymers

The biodegradable polymer may be a bulk-eroding polymer such as apolyester polymer.

The polyester polymer may comprise lactide, glycolide, or a combinationthereof as a co-block polymer, such as wherein the percentage of lactideis from about 65% to about 85% w/w of the co-block polymer and whereinthe percentage of glycolide is from about 15% to about 35% w/w of theco-block polymer. More specifically, the polyester polymer is selectedfrom the group consisting of poly(D,L-lactide),poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide),poly(D,L-lactide-co-glycolide), and combinations thereof.

Biodegradable polymers that are applicable include those comprised oflactide and glycolide species, including but not limited to:polylactides, polyglycolides, poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), poly(D,L-lactide), andpoly(ε-caprolactone).

Polylactides (PLA), also called polylactic acids, are polyesters on thebasis of lactic acid. Polylactides are polyhydroxyacids. They arebiocompatible and biodegradable. The lactide may comprise a racemicmixture of D and L-isomers, providing a D,L-lactide. The lactide mayalso be obtained wherein the D:L ratio is different from 1:1 (enrichedmixtures). Moreover, it is possible to prepare either of the single D-or L-enantiomers in substantially pure form (>99.99% by weight). Amongthe two enantiomeric forms of the lactide, the L-isomer is preferred. Inthe case of enriched mixtures of lactides used in preparinglactide-containing biopolymers, those enriched in the L-enantiomer arepreferred, preferably with an L:D ratio of the two enantiomers rangingfrom 51:49 to 99.99:0.01 by weight, such as 60:40, 75:25, 80:20, or90:10. As used herein, when a polymer is designated as comprisingL-lactide, at least 60, or at least 75, or at least 80, or at least 90%of the lactide therein comprises the L-enantiomer.

Polylactides may also include block copolymers comprising blocks ofL-lactide and D,L lactide.

The properties of polylactides depend primarily on their molecularweight, degree of chirality, degree of crystallinity, and the portion ofcopolymers, if applicable. The glass transition temperature, the meltingtemperature, the tensile strength and the E-module of the polylactidesincrease, but the breaking elongation decreases as the molecular weightof the polylactides increases.

Polylactides can be obtained by ring-opening polymerization of lactide.The ring-opening polymerisation is performed at temperatures between 140and 180° C. in the presence of stannous octoate catalyst. Polylactideswith high molecular weight can be easily produced by this method. Inaddition, high molecular weight and pure polylactides can be generateddirectly from lactic acid by the so-called polycondensation.

Polylactide-co-glycolides (PLGA) are biodegradable polymers thatcomprise (or consist of) lactic acid linked with glycolic acid, therespective percentages of which play a major role in the rate of drugrelease. The ratio of lactide to glycolide may be from 90:10 to 10:90,with ratios of from 20:80 to 80:20 being preferred and ratios of from40:60 to 60:40 being more preferred, and a ratio of 50:50 being mostpreferred. Lactide is optically active, and any proportions of D and Lisomers may be present in the copolymer, ranging from pure D-lactide topure L-lactide, with racemates comprising 50% D-lactide and 50%L-lactide.

The biodegradable polymer may comprise a surface-eroding polymer; suchas wherein the biodegradable polymer comprises a polyanhydride polymer.

The term “polyanhydride” refers to a polymer that is derived from thecondensation of carboxylic acids or carboxylic acid derivatives suchthat repeating units of the resulting polymer are linked by anhydride(—C(═O)—O—C(═O)—) groups. Polyanhydrides can be prepared by condensingdiacids or by condensing anhydride prepolymers, as is known in the art.

Polyanhydrides are useful polymers for drug delivery systems because oftheir biodegradability and biocompatibility. Amphiphilic polyanhydridemicrospheres (PAMs) are chemically and structurally distinct from otherpolymer or lipid based particle delivery systems. PAMs are solid,surface-eroding particles that encapsulate small molecules or proteinswithin the polymer matrix, providing sustained release of drug as thePAM erodes. Their degradation pattern of surface erosion makes themsuitable for stable drug release applications.

The term “carboxylic anhydride” refers to a compound that contains ananhydride (— C(═O)—O—C(═O)—) group. A carboxylic anhydride typicallycontains only one anhydride group per molecule. Carboxylic anhydridescan be formed by the condensation of two carboxylic acids. Carboxylicanhydrides that can be used in conjunction with the methods describedherein include bis-alkyl carboxylic anhydrides, bis-aryl carboxylicanhydrides, and mixed anhydrides. Examples include, but are not limitedto acetic anhydride, trifluoroacetic anhydride, and benzoic anhydride.Mixed anhydrides can also be employed, such as acetic benzoic anhydride,which is the condensation product of acetic acid and benzoic acid.

Polyanhydride polymers can include anhydride polymers comprising1,ω-bis(carboxy)(C₂-C₁₀)alkane units, preferably1,ω-bis(carboxy)(C₃-C₁₀)alkane units such as sebacic anhydride, or1,ω-bis(carboxyphenoxy)(C₂-C₁₀)alkane units, such as1,3-bis(p-carboxyphenoxy)propane (CPP),1,6-bis-(p-carboxy-phenoxy)hexane (CPH), or1,8-bis(carboxyphenoxy)-3,6-dioxaoctane (CPTEG), or combinationsthereof.

They may also comprise copolymers comprising1,ω-bis(carboxy)(C₂-C₁₀)alkane units and1,ω-bis(carboxyphenoxy)(C₂-C₁₀)alkane units, such as copolymers derivedfrom copolymerization of sebacic anhydride and CPP, CPH and/or CPTEG.The ratio of 1,ω-bis(carboxy)(C₂-C₁₀)alkane to1,ω-bis(4-carboxyphenoxy)(C₂-C₁₀)alkane units in the microsphere can beabout 90:10 to about 50:50 to about 10:90, or any ratio in between, suchas 85:15, 80:20, 75:25, 70:30, 60:40, or 55:45, or the reverse of suchratios.

The microspheres may comprise a single polylactide orpolylactide-co-glycolide or polyanhydride, or they may comprise mixturesthereof, such as a mixture of two different polymers in the same class,such as a mixture of two different polylactides (e.g. a mixture ofpoly(D,L-lactide) and poly(L-lactide), or two differentpolylactide-co-glycolides, or a mixture of two different polyanhydrides,or a mixture of a polylactide and a polylactide-co-glycolide, or amixture of a polylactide and a polyanhydride, or a mixture of apolylactide-co-glycolide and a polyanhydride.

The percentage of biodegradable polymer may be from about 50% to about95% w/w of each microsphere, from about 55% to about 90% w/w of eachmicrosphere, from about 60% to about 85% w/w of each microsphere, fromabout 65% to about 80% w/w of each microsphere, or from about 60% toabout 70% w/w of each microsphere.

Cellulose-Derived Material

The composition comprises microspheres comprising a biodegradablepolymer, an active ingredient, and a cellulose-derived material (CDM)wherein the percentage vf_CDM is from about 0.5% to about 6% w/w of eachmicrosphere. The CDM includes cellulose ethers or cellulose esters.

Cellulose ethers include ethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, and microcrystalline cellulose.Cellulose esters include cellulose acetate, cellulose acetate phthalate,and hydroxypropyl methyl cellulose phthalate. Preferably compositions ofthe present disclosure comprise ethyl cellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, or variations or combinations thereof. More preferably, thecompositions comprise ethyl cellulose.

Cellulose ethers such as ethyl cellulose do not occur naturally and aresynthetically produced by heating cellulose with caustic solution (e.g.a solution of sodium hydroxide) and treating it an alkyl halide. In thesubstitution reaction that follows, the hydroxyl residues (—OHfunctional groups) are replaced by alkoxide (—OR groups). Differentkinds of ethyl cellulose can be prepared depending on the number ofhydroxyl groups substituted. Cellulose is a polymer consisting ofnumerous linked glucose molecules, each of which exposes three hydroxylgroups. The Degree of Substitution (DS) of a given form of ethylcellulose is defined as the average number of substituted hydroxylgroups per glucose. The theoretical maximum is thus a DS of 3.0, howevermore typical values are 1.3-2.6, corresponding to 43 to 87% of availablehydroxyl groups substituted, preferably 44 to 51%, or 48 to 50%. Ethylcellulose preparations can also differ in the average length of theirpolymer backbones, which relates both to molecular weight and viscosity.Cellulose esters can be prepared similarly, except the cellulose istreated with acid derivatives such as acid chlorides or anhydrides.

Ethyl cellulose compositions can be characterized by the kinematicviscosity of a standard solution of the polymer. The viscosity of afluid is a measure of its resistance to gradual deformation by shearstress or tensile stress. For liquids, it corresponds to the informalconcept of “thickness”; for example, honey has a much higher viscositythan water. The dynamic (shear) viscosity of a fluid expresses itsresistance to shearing flows, where adjacent layers move parallel toeach other with different speeds. The kinematic viscosity (also called“momentum diffusivity”) is the ratio of the dynamic viscosity μ to thedensity of the fluid. The term “viscosity grade” with regard to ethylcellulose arises from the measurement (ASTM D914) of the viscosity of a5% solution of the polymer in 80:20 toluene/ethanol. Higher viscositygrades correspond generally to higher polymer molecular weight. Ethylcellulose viscosity grades range from about 3 to about 110 cP,preferably from a lower limit of 4, 10, 20, 40 or 50 cP to an upperlimit of 25, 40, 50 or 100 cP.

Compositions described herein include those wherein thecellulose-derived material (CDM) comprises a viscosity fraction of about0.1% to about 5%; wherein the viscosity fraction is calculated accordingto the equation

vf_CDM=η_inh_CDM*(f_CDM)/[η_inh_CDM*(f_CDM)+η_inh_Pol*(f_Pol)]*100  (Eq.1)

wherein vf_CDM=the viscosity fraction vf_CDM in the polymer matrix;η_inh_CDM=the inherent viscosity of the CDM; η_inh_Pol=the inherentviscosity of the polymer, f_CDM=the fraction vf_CDM in the polymermatrix; and f_Pol=the fraction of polymer in the polymer matrix. Use ofthis equation is described in more detail in Example 1 for the specificcellulose-derived material ethyl cellulose.

Notable embodiments include those wherein the CDM, such as ethylcellulose, comprises a viscosity fraction of about 0.1% to about 5%;about 0.5% to about 3.5%; about 0.2% to about 2%; about 0.3% to about1%; or about 0.5% to about 2%.

In preferred embodiments, at least 90% of the plurality of microsphereshave particle diameters from about 40 μm to about 70 μm, from about 45μm to about 65 μm, from about 50 μm to about 60 μm, from about 50 μm toabout 70 μm, from about 40 μm to about 55 μm, from about 60 μm to about100 μm, from about 65 μm to about 95 μm, from about 70 μm to about 90μm, from about 70 μm to about 85 μm, from about 70 μm to about 80 μm, orfrom about 75 μm to about 85 μm.

Other water-insoluble materials included in the matrix of themicrospheres in the compositions may comprise waxes, fatty acids orderivatives thereof such as esters or salts, lipids, or combinations orvariations thereof. Waxes include any wax-like material suitable for usewith the active ingredient. Examples of suitable waxes include, but arenot limited to, ceresine wax, beeswax, ozokerite, microcrystalline wax,candelilla wax, montan wax, carnauba wax, paraffin wax, cauassu wax,Japan wax, and Shellac wax. Suitable lipid materials are generally solidat room temperature and may have a melting temperature at or above about45° C. Examples of suitable lipid materials include, but are not limitedto, glycerol fatty acid esters, such as triacylglycerols (e.g.,tripalmitin, tristearin, glyceryl trilaurate, coconut oil), hydrogenatedfats, ceramides, and organic esters from and/or derived from plants,animals, or minerals.

Examples of suitable fatty acids or derivatives thereof include but arenot limited to, stearic acid, sodium stearate, magnesium stearate,glyceryl monostearate, cremophor (castor oil), oleic acid, sodiumoleate, lauric acid, sodium laurate, myristic acid, sodium myristate,vegetable oils, coconut oil, mono-, di-, tri-glycerides, stearylalcohol, and sorbitan esters such as sorbitan monolaurate (Span 20) orsorbitan monooleated (Span 80). For example, in certain embodiments, thefatty acid may be a combination of stearic acid and glyceryl monostearate.

Therapeutic Agents

The PLA-, PLGA-based and/or polyanhydride-based microspheres of thisinvention can be loaded with virtually any pharmacologically activesubstance in order to administer the pharmacologically active substance,i.e. a therapeutic agent or a diagnostic agent, to a subject such as amammal, including a human subject. The microspheres described hereinprovide for sustained release of a therapeutic agent as the microsphereerodes, for example within a subject requiring treatment, or within atarget parasite in the case of antiparasitic compositions.

The microsphere composition includes those wherein the percentage ofactive therapeutic agent is from about 10% to about 40% w/w of eachmicrosphere.

Notable compositions include those wherein the active therapeutic agentis an integrase inhibitor, an antiparasitic, a steroid hormone asomatostatin analogue a peptide; and/or wherein the active therapeuticagent is an organic compound having a molecular weight of less than 1000daltons.

Integrase inhibitors, also known as integrase strand transfer inhibitors(INSTIs), are a class of antiretroviral drug designed to block theaction of integrase, a viral enzyme that inserts the viral genome intothe DNA of the host cell. Since integration is a vital step inretroviral replication, blocking it can halt further spread of thevirus. Integrase inhibitors were initially developed for the treatmentof HIV infection, but they could be applied to other retroviruses. Sinceintegrase inhibitors target a distinct step in the retroviral lifecycle, they may be taken in combination with other types of HIV drugs tominimize adaptation by the virus. They are also useful in salvagetherapy for patients whose virus has mutated and acquired resistance toother drugs. Example integrase inhibitors include dolutegravir,elvitegravir, raltegravir, BI 224436, bictegravir (GS-9883),cabotegravir and MK-2048.

Antiparasitics are a class of medications which are indicated for thetreatment of parasitic diseases, such as those caused by helminths,amoebas, ectoparasites, parasitic fungi, and protozoa, among others.Antiparasitics target the parasitic agents of the infections bydestroying them or inhibiting their growth; they are usually effectiveagainst a limited number of parasites within a particular class.Broad-spectrum antiparasitics, analogous to broad-spectrum antibioticsfor bacteria, are antiparasitic drugs with efficacy in treating a widerange of parasitic infections caused by parasites from differentclasses. Example antiparasitics include the broad spectrum antiparasiticnitazoxanide; antiprotozoals such as melarsoprol and eflornithine (fortreatment of sleeping sickness caused by Trypanosoma brucei),metronidazole (for vaginitis caused by Trichomonas), Tinidazole (forintestinal infections caused by Giardia lamblia), and miltefosine (forthe treatment of visceral and cutaneous leishmaniasis, and currentlyundergoing investigation for Chagas disease); antinematodes such asmebendazole and pyrantel pamoate (for most nematode infections;thiabendazole (for roundworm infections); diethylcarbamazine (fortreatment of Lymphatic filariasis) and ivermectin (for prevention ofriver blindness); anticestodes such as albendazole (broad spectrum),niclosamide and praziquantel (for tapeworm infections); antiamoebicssuch as rifampin and amphotericin B; and antifungals such as fumagillin(for microsporidiosis).

Antiparasitic and/or antimicrobial compounds can be encapsulated intothe microspheres, thereby allowing the compounds to be slowly releasedafter they are internalized by parasites as the particles degrade. Theability of the PAMs to slowly erode and release the cargo molecules in acontrolled manner allows for specificity against both adult nematodesand the symbiotic bacteria Wolbachia. The microspheres can degrade bybulk erosion or surface erosion in the presence of the parasite over aperiod of time to release the active agents from the interior of themicrospheres, thereby killing the parasite or inhibiting thereproduction of the parasite. Administration of the microspheresdescribed herein can therefore interrupt the life cycle of the nematodenot by just reducing microfilaria load, but by directly increasingmortality in the adult population.

A steroid hormone is a steroid that acts as a hormone. Steroid hormonescan be grouped into two classes: corticosteroids and sex steroidsdivided into types according to the receptors to which they bind:glucocorticoids, mineralocorticoids (corticosteroids), androgens,estrogens, and progestogens (sex steroids). Vitamin D derivatives are asixth closely related hormone system with homologous receptors. Theyhave some of the characteristics of true steroids as receptor ligands.Steroid hormones help control metabolism, inflammation, immunefunctions, salt and water balance, development of sexualcharacteristics, and the ability to withstand illness and injury. Theterm steroid describes both hormones produced by the body andartificially produced medications that duplicate the action for thenaturally occurring steroids. Synthetic steroids and sterols have alsobeen contrived. Most are steroids, but some non-steroidal molecules caninteract with the steroid receptors because of a similarity of shape.Examples of synthetic steroid hormones include glucocorticoids such asalclometasone, prednisone, dexamethasone, triamcinolone, and cortisone;mineralocorticoids such as fludrocortisone; vitamin D analogs such asdihydrotachysterol; androgens (also known as anabolic-androgenicsteroids or anabolic steroids) such as oxandrolone, oxabolone,testosterone, and nandrolone; estrogens such as diethylstilbestrol (DES)and estradiol; and progestins such as norethisterone,medroxyprogesterone acetate, etonogestrel and hydroxyprogesteronecaproate.

Somatostatin analogs are used for treatment of tumors secretingvasoactive intestinal peptide, carcinoid tumors, glucagonomas andvarious pituitary adenomas. They are also used to treat acromegaly (acondition in where there is oversecretion of growth hormone in anadult). Representative somatostatin analogs include octreotide,pasireotide, lanreotide and veldoreotide (COR-005).

Pharmaceutical Compositions

The pharmaceutical compositions of the invention include a microsphereor composition described herein, a therapeutic agent as an activeingredient and optionally, a pharmaceutically acceptable carrier and/orexcipient or diluent such as a solvent.

Solvents that are applicable to the present disclosure include thoseused in parenteral drug formulation, including, but not limited to:Class II solvents such as acetonitrile, chloroform, dichloromethane,hexane, methanol, tetrahydrofuran, toluene, and xylene; and Class IIIsolvents such as acetone, butyl acetate, ethanol, dimethyl sulfoxide,and ethyl acetate.

The drug delivery systems or devices or pharmaceutical compositions ofthis invention encompass compositions made by admixing a microsphere orcomposition of this invention comprising a therapeutic agent andoptionally a pharmaceutically acceptable carrier and/or excipient ordiluent. Such compositions are suitable for pharmaceutical use in ananimal or human subject.

In some embodiments, this invention provides a pharmaceuticalcomposition including a microsphere described herein, and optionally apharmaceutically acceptable carrier and/or excipient. The polymersdescribed herein can be combined with a cellulose-derived material and atherapeutic agent in intimate admixture in microspheres describedherein, optionally with a suitable pharmaceutical carrier and/orexcipient according to conventional pharmaceutical compoundingtechniques. In some embodiments, this invention provides apharmaceutical composition including a microsphere described herein, afurther therapeutic agent and optionally a pharmaceutically acceptablecarrier and/or excipient. The further therapeutic agent is not containedwithin the microsphere to provide, for example, compositions with bothan immediate release of a therapeutic agent and a sustained release of atherapeutic agent. The further therapeutic agent may be the same as ordifferent from the therapeutic agent contained in the microsphere. Anycarrier and/or excipient suitable for the form of preparation desiredfor administration is contemplated for use with the microspheresdisclosed herein. The compositions may be prepared by any of the methodswell-known in the art of pharmacy.

In some of these embodiments, the pharmaceutically acceptable excipientincludes a salt or a diluent.

In some embodiments, the composition is formulated for parenteral (suchas intravenous) administration or oral administration and includes thecomposition and at least one member selected from the group consistingof an aqueous solution and a buffer solution.

In some embodiments, this invention provides compositions furtherincluding a pharmaceutical surfactant.

In some embodiments, this invention provides compositions furtherincluding a cationic surfactant selected from the group consisting ofbenzalkonium chloride, benzethonium chloride, and cetrimide.

In some embodiments, this invention provides compositions furtherincluding an anionic surfactant selected from the group consisting ofdocusate sodium and sodium lauryl sulfate.

In some embodiments, this invention provides compositions furtherincluding a non-ionic surfactant selected from the group consisting ofglyceryl monooleate, sorbitan esters, polyoxyethylene sorbitan fattyacid esters, and polyoxyethylene alkyl ethers. In some embodiments, thenon-ionic surfactant is a sorbitan ester selected from the groupconsisting of sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate, sorbitan sesquioleate, andsorbitan trioleate. In someembodiments, the non-ionic surfactant is a polyoxyethylene sorbitanfatty acid ester selected from the group consisting of polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, andpolysorbate 85. In some other embodiments, the non-ionic surfactant is apolyoxyethylene alkyl ether selected from the group consisting ofpolyethylene glycol monocetyl ether, polyethylene glycol monolaurylether, polyethylene glycolmonooleyl ether, and polyethylene glycolmonostearyl ether. In some embodiments, the poloxamer is selected fromthe group consisting of P124, P188, P237, P338, and P407.

In some embodiments, this invention provides compositions furthercomprising a cryoprotectant. In some embodiments, the cryoprotectant isselected from the group consisting of glucose, sucrose, trehalose,lactose, sodium glutamate, PVP, HPβCD, CD, glycerol, maltose, mannitol,and saccharose.

Administration of an appropriate amount of the pharmaceuticalcomposition may be by any means known in the art. The pharmaceuticalcompositions include compositions suitable for parenteral, pulmonary,nasal, rectal, topical, or oral administration. The most suitable routeof administration in any given case will depend in part on the natureand severity of the conditions being diagnosed. Notably, thecompositions are suitable for parenteral (systemic) administration. Thecompositions may be administered by injection, e.g., via a syringe,subcutaneously, intravenously, intramuscularly, intraperitoneally,subconjunctivally, intravitreally. The administration may includedelivery into the synovial space (e.g., for the treatment of arthritis)or intrathecal injection (e.g., for the treatment of brain diseases).Other preferred compositions include compositions suitable for othersystemic administration including enteral, oral, rectal, sublingual, orsublabial administration.

The compositions, agents, and microspheres described herein arepreferably administered parenterally. Solutions or suspensions of thesemicrospheres can be prepared in water suitably mixed with a surfactantsuch as the pharmaceutically acceptable surfactants described above.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations may contain a preservative toprevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringeability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Injection solutions and suspensions can be prepared from sterilepowders, granules, and tablets of the kind described below. Formulationssuitable for parenteral administration, such as, for example, byintra-articular (in the joints), intravenous, intramuscular,intradermal, intraperitoneal, and subcutaneous routes, include aqueousand non-aqueous, isotonic sterile injection solutions, which can containantioxidants, buffers, bacteriostats, and solutes that render theformulation isotonic with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.

Compositions for systemic administration include, but are not limitedto, dry powder compositions consisting of the composition as set forthherein and optionally the powder of a suitable carrier and/or excipient.The compositions and/or drug delivery systems for systemicadministration can be represented by, but not limited to, tablets,capsules, caplets, pills, syrups, solutions, and suspensions.

Compositions for pulmonary administration include, but are not limitedto, dry powder compositions comprising the powder of a microspheredescribed herein with a therapeutic agent, and optionally the powder ofa suitable carrier and/or lubricant. The compositions for pulmonaryadministration can be inhaled from any suitable dry powder inhalerdevice known to a person skilled in the art.

Formulations suitable for oral administration can consist of (a) liquidsolutions, suspensions, emulsions, or gels, such as an effective amountof the microsphere dispersed in diluents, such as water, saline or PEG400; optionally with excipients such as surfactants, cosolvents and thelike; and (b) capsules, sachets or tablets, each containing apredetermined amount of the active ingredient, as liquids, solids,granules or gelatin. Tablet forms can include one or more of lactose,sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potatostarch, microcrystalline cellulose, gelatin, colloidal silicon dioxide,talc, magnesium stearate, stearic acid, and other excipients, colorants,fillers, binders, diluents, buffering agents, moistening agents,preservatives, flavoring agents, dyes, disintegrating agents, andpharmaceutically compatible carriers.

In the pharmaceutical compositions of this invention for parenteral(subcutaneous, intramuscular, intravenous), oral, sublingual, local orrectal administration, microspheres as described herein, can beadministered to animals and humans in unit dosage forms ofadministration mixed with conventional pharmaceutical carriers. Theappropriate unit forms of administration include oral forms such astablets, gelatin capsules, powders, granules and solutions orsuspensions to be taken orally, sublingual and buccal forms ofadministration, aerosols, implants, subcutaneous, intramuscular,intravenous, intranasal or intraocular forms of administration andrectal forms of administration.

Kits providing a unit dosage of the pharmaceutical compositions setforth herein are contemplated as within this invention. Kits providingmany unit dosages of the compositions set forth herein are contemplatedas within this invention. Still further, kits providing several unitdosages of the compositions set forth herein are contemplated as withinthis invention. In some embodiments, the kits of this invention includea unit dosage of a pharmaceutical compositions set forth herein. Incertain embodiments, the kits of this invention include many unitdosages of a pharmaceutical compositions set forth herein. In certainother embodiments, the kits of this invention include a unit dosage of apharmaceutical composition set forth herein.

Drug delivery devices of the invention comprise powders, microspheres,tablets, gelatin capsules, pills, capsules, caplets, sachets and thelike as described herein comprising a microsphere described herein. Drugdelivery devices also include shaped articles comprising themicrospheres, including for example films, disks or rods. Such shapedarticles may be suitable for implantation in a subject's body, such assubcutaneously. Drug delivery devices also include devices configured todeliver one or more unit dosages of a pharmaceutical compositioncomprising a microsphere described herein. Such devices include forexample, syringes, aerosol sprayers, pump sprayers, applicators, orinhalers.

The microspheres described herein provide benefits to pharmaceuticalformulations including decreased deviation in mean microsphere diameterduring fabrication, improved entrapment efficiency and enhancedhydrophobicity, improved microsphere stability in terms of dissolutionbehavior and thermal resistance and/or the ability to adjust drugrelease rate. These benefits are demonstrated in the following Examples.

Decreased Deviation in Mean Microsphere Diameter During Fabrication

Examples 1-5 and 13 illustrate how ethyl cellulose improves monodispersemicrosphere size variation during fabrication, especially at high drugloadings. Without ethyl cellulose, the high drug content makes itdifficult for droplets to harden and for microspheres to retain aspherical shape during manufacture. It is postulated that thewater-insoluble binder intercalates the polymer chains and assists inshape retention. Other technologies cannot achieve tight sizedistributions easily because particle size distributions used withemulsion processes are broad. Some can make very small particles withlow drug loading, but the size distribution at that small size is toobroad for the injectate (particles+injection vehicle) to performreproducibly in terms of overall viscosity and flowability. Precisionparticle fabrication technology is unique because it can achieve smallparticle size. By controlling droplet size, precision particlefabrication technology can predict, and resolve, issues around poorentrapment efficiency that other technologies cannot. Competingformulations exhibit drug burst release for the exact same reasons theyget poor loading during manufacturing; lack of control over particlesize. With inclusion of ethyl cellulose, the advantages of precisionparticle fabrication are amplified in terms of maintaining tight sizedistributions with no drug burst at drug loadings over 30% w/w.

Improved Entrapment Efficiency and Enhanced Hydrophobicity

Examples 2-3 illustrate how ethyl cellulose improves drug entrapmentduring fabrication at high loadings. Without ethyl cellulose, thepolymer matrix will sometimes not maintain the ability to localize druginside the droplet during hardening, especially if the drug has lowsolubility in water. It is postulated that the water insoluble materialintercalates the polymer chains and assists shape retention anddecreased diffusion of the drug from the hardening polymer droplet. Inaddition, because ethyl cellulose is extremely hydrophobic (i.e. waterinsoluble), it may act as a barrier to drug escape by occupying lessfree volume at the discontinuous-continuous (droplet-water) phaseinterface.

Improved Microsphere Stability in Terms of Dissolution Behaviour andThermal Resistance

Examples 5 and 12 illustrate how ethyl cellulose improves stability ofthe microsphere product at elevated temperatures. Many controlledrelease polymers and drugs have recommended storage temperatures of −20°C. or below to prevent degradation. Polymers in particular are subjectto slow hydrolysis from moisture in the air, and drugs are subject todegradation by a number of means, including oxidation. With ethylcellulose, polymers and drugs that both have recommended low storagetemperatures can safely be stored at 40° C. and 75% RH for extendedperiods and exhibit (1) no drug degradation, (2) reproducibledissolution kinetics, and (3) reproducible glass transition temperatures(Tg) of the microspheres, indicating resistance to thermal events.Example 5 suggests that benefits of ethyl cellulose inclusion areadvantageous at an ethyl cellulose viscosity fraction of no more than6%.

Ability to Adjust Drug Release Rate

Examples 6-11 highlight how native ethyl cellulose viscosity has theability to adjust drug release rate. In some instances, the viscosity ofethyl cellulose will be inversely proportional to release rate of drugjust as seen with any controlled release polymer (lower viscosity, orlower molecular weight, will enable faster release rate, and higherviscosity or molecular weight, will enable slower release rate). Inother instances, this logical phenomenon may not be observed. Althoughnot limited by theory, it is speculated that the polymer chemistryinfluences whether logical adjustments in release rate can be achievedin binary systems consisting of ethyl cellulose and another polymer.Examples 6-11 generally indicate that (1) for polymers without aglycolide component, ethyl cellulose viscosity can alter release rate,but not in a logical, inversely proportional manner, and (2) forpolymers with a glycolide component, release rate is in fact inverselyproportional to ethyl cellulose viscosity.

EXAMPLES Formulations Used

The following microsphere formulations were manufactured with precisionparticle fabrication technology described in U.S. Pat. Nos. 6,669,961,7,309,500, and 7,368,130, all of which are incorporated by reference.This particle fabrication technology highlights the advantages of ethylcellulose inclusion. Details about each formulation (including polymertype, polymer viscosity, ethyl cellulose viscosity, ethyl cellulosefraction, ethyl cellulose viscosity fraction, and drug loading) aretabulated in Tables 1-13 below. Abbreviations for polymers used arelisted in Table A. The commercial source for all PLAs and PLGAs wasEvonik Industries, Essen, Germany. The ethylcellulose was sourced fromSigma Aldrich in St. Louis, MO. The compositional and physicalproperties for the polymers are contained in the “polymer chemistry,co-block ratio, polymer inherent viscosity” columns in the formulationtables, and the ethyl cellulose grade is contained in the “kinematicviscosity” column in the same formulation tables. Properties for drugsused are listed in Table B.

Table A Abbreviation Polymer Chemistry P-DLL-GPoly(D,L-lactide-co-glycolide) P-LL-G Poly(L-lactide-co-glycolide) P-DLLPoly(D,L-lactide) P-LL-DLL Poly(L-lactide-co-D,L-lactide) EC Ethylcellulose

TABLE B Drug Drug Molecular Water ID Name Classification Weight logPSolubility A Elvitegravir Integrase 448 Da 4.67 <0.003 mg/mL inhibitor B— Antiparasitic 581 Da 3.66 <0.010 mg/mL C Etonogestrel Steroid 324 Da3.40 <0.007 mg/mL hormone D Octreotide Somatostatin 1141 Da  0.43    >10mg/mL analogue

Particle Size and Photographs

Microsphere size was determined via either microscopy or particle sizeanalyzer. For sizes determined by microscopy, a small (about 2 mg)sample of microspheres was placed on a glass slide and wetted to promoteparticle dispersion. The slide was placed under a microscope objectiveand visualized with paired software. The software had been previouslycalibrated with an external scalebar using multiple magnifications.Particle size was quantified by measuring the diameter of a subset ofmicrospheres with the software algorithms and averaging themeasurements. Photographs were taken by creating a still image of themicrospheres while on the glass slide. For sizes determined with aparticle analyzer, a small sample (about 10 mg) of microspheres wasdispersed into an Isotonic solution (about 10 mL). The suspension wasplaced onto the stage of a Coulter Multisizer M3 fitted with a 560micrometer aperture. The analyzer software was then used to sample thesuspension and create a volume-based curve denoting the distribution ofparticle sizes within the measurement period, which was typically 30seconds.

Drug Release Determination

The release of drugs from the microspheres was determined according tothe following general procedure.

Microspheres containing drug were manufactured according to thepre-determined formulation following the procedures described inExample 1. Following lyophilization, microspheres were divided intosamples for dissolution testing at multiple timepoints. For instance,some microspheres were tested immediately upon manufacture (e.g. T=0Months), and some were stored at ICH temperatures (i.e. 40 degreescentigrade/75% relative humidity) after longer storage periods like T=1Week, T=4 Weeks/1 month or T=6 months. After storage for the timeindicated in the Figures, samples were removed from the incubator,allowed to cool down to room temperature and sampled to determine therelease profile. Drug release was quantified by placing a small amountof microspheres (about 10 mg) into a dissolution medium and volumepreviously determined to provide sink conditions for the activepharmaceutical ingredient. For the active pharmaceutical ingedients(APIs) tested in examples 1-12, the dissolution medium consisted of a0.1% sodium lauryl sulfate (SLS) solution in either 20 or 60 mL glassscintillation vials at 40 degrees centigrade, with stirbars rotating at300 rpm. The dissolution medium was sampled at predefined timepointsover several days or months, where after each sampling the medium wasrefreshed so volume remained constant. Notably the dissolution study fora given sample was conducted over multiple days after removal fromstorage. For example, a given formulation such as Sample 5.1 (FIG. 5A)was stored for 0 weeks, 1 week or 4 weeks at 40° C., after which sampleswere removed from the chamber and the dissolution was followed for sevendays after removal from storage to provide the cumulative release plotsindicated. After each sampling, the dissolution supernatant was filteredand analyzed via high performance liquid chromatography for drugconcentration, after which total mass release was calculated bymultiplying the concentration by dissolution volume. The mass releasedat each timepoint was then normalized to the total mass encapsulatedwithin the microsphere, denoted as cumulative release. Drug contentwithin the microsphere was determined by dissolving a defined mass ofmicrospheres (about 10 mg) in a solvent (about 10 mL), and analyzing thecontent of that extracted sample.

Example 1

Monodisperse microspheres without ethyl cellulose were fabricated from aproprietary process previously described. Briefly, rawpoly(D,L-lactide-co-glycolide) (P-DLL-G) 65:35 was added todichloromethane (DCM) at a concentration of 7% w/v in a 20 mL glassscintillation vial and vortexed until dissolved. Drug A was thenco-dissolved with the polymer solution at 3% w/v, bringing the totalsolids content in the vial to 10% w/v and the theoretical drug loadingto 30% w/w. The polymer solution was then loaded into a plasticluer-lock syringe which is affixed to a precision syringe pump, andconnected to the custom particle fabrication nozzle with small volumePTFE tubing. The polymer solution was flowed at a rate of 5 mL/hrthrough the nozzle, which was excited at a 4 kHz frequency via vibratorymechanism. The droplets, which were typically around 20-30 μm indiameter, fell into a 2000 mL glass beaker of deionized (DI) watersupplemented with 0.5% w/v poly(vinyl alcohol) (PVA), which served as asurfactant and prevented droplet aggregation. Following ejection of theentire syringe contents, the droplets were stirred at 75 rpm for 3 hourswith a stir bar that spans the diameter of the beaker to aid inextraction of the DCM into the PVA solution. Following solventextraction, stirring was halted, the stir bar was removed with amagnetic wand, and the particles were allowed to settle to the beakerfloor, which was completed in 10 minutes. The Water/PVA/DCM supernatantwas then removed with a glass pipet and disposed of in an appropriatewaste container, and the remaining particles were washed with DI wateronce before being concentrated into a 50 mL centrifuge tube. The wettedparticles were placed in a −80° C. freezer until frozen, and thentransferred to a lyophilization chamber at 0.028±0.002 bar and −50±2° C.for 48 hours. When dry, the particle vials were lightly agitated by handto ensure a flowable powder. Drug content was determined by dissolvingdried microsphere samples (about 10 mg) in DCM and quantifying on a highperformance liquid chromatography (HPLC) system outfitted with a C18column. Actual drug content following analysis was found to be 29.4%,making the actual polymer content 70.6%. A small sample was taken fromthe microsphere powder to obtain microscope images and size distributionwith a Coulter Multisizer M3 (Sample 1.1 in FIG. 1A).

Monodisperse microspheres with ethyl cellulose were fabricated in themanner previously described, only with ethyl cellulose dissolved in thepolymer solution such that the theoretical drug loading was 30% w/w, theethyl cellulose content was 1% w/w, and the polymer content was 69% w/w.Drug content was determined by dissolving dried microsphere samples(about 10 mg) in DCM and quantifying on a high performance liquidchromatography (HPLC) system outfitted with a C₁₈ column. Actual drugcontent following analysis was found to be 29.4%, making the actualpolymer and ethyl cellulose content 69.6% and 1.0%, respectively. Asmall sample was taken from the microsphere powder to obtain microscopeimages and size distribution with a Coulter Multisizer M3 (Sample 1.3 inFIG. 1C).

The content of ethyl cellulose in the controlled release matrix can bedenoted as the inherent viscosity fraction, where the inherent viscosityfraction consists of a weighted average of the polymer inherentviscosity and the ethyl cellulose inherent viscosity fraction. Simply,the viscosity fraction is the contribution of ethyl cellulose to theoverall viscosity of the controlled release matrix during microspheresynthesis. Often, the viscosity of ethyl cellulose is reported assolution viscosity, not as inherent viscosity, and it must be convertedbefore being weighted with the polymer inherent viscosity. In Sample1.3, ethyl cellulose was said to have a viscosity of 22 cP in a 5% w/v80:20 toluene:ethanol solution (i.e. its viscosity grade), and P-DLL-Gwas said to have an average viscosity of 0.4 dL/g. They are combined ina microsphere such that the whole particle formulation is comprised of1.0% w/w ethyl cellulose, 29.4% drug, and 69.6% polymer. Knowing thatthe viscosity of an 80:20 toluene:ethanol mixture is 0.527 cP, one mustcalculate the inherent viscosity fraction of the polymer-ethyl cellulosesystem (not including drug). First, the kinematic viscosity of the ethylcellulose solution must be converted to inherent viscosity of the ethylcellulose itself. The inherent viscosity can be calculated using therelation in Equation 2 wherein η_inh=the inherent viscosity of thematerial (in dL/g); η_solute=the kinematic viscosity of the solution (incP); η_solvent=the kinematic visocity of the solvent (in cP);c_solution=the concentration of the solution (in g/dL):

η_inh=ln(η_solution/η_solvent)/c_solution  (Eq. 2)

Accordingly, the inherent viscosity of the ethyl cellulose entity itselfis determined to be η_inh=ln (22 cP/0.527 cP)/5 g/dL=0.746.

Though the absolute ethyl cellulose content is 1.0% w/w with respect tothe whole microsphere formulation (EC+Drug+PDLLG), assuming no polymeror ethyl cellulose was lost in fabrication, the fraction of ethylcellulose with respect to non-drug components is based only ontheoretical contribution of those two components. In Sample 1.3, thetheoretical composition vf_EC and polymer were 1.0% and 69%respectively, thus ethyl cellulose is 1.0%/(1.0%+69.0%)*100=1.43% of thecontrolled release matrix component (EC+PDLLG), with the P-DLL-Gconstituting the remaining 98.57%. Thus, the viscosity fraction of ethylcellulose in the controlled release component can be calculated toaccording to the relationship in Eq. 2, wherein vf_EC=the viscosityfraction of ethyl cellulose in the controlled-release component;η_inh_EC=the inherent viscosity of ethyl cellulose; η_inh_PDLLG=theinherent viscosity of the polymer, P-DLL-G; f EC=the fraction of ethylcellulose in the controlled release component; and f_PDLLG=the fractionof polymer (P-DLL-G) in the controlled release component

vf_EC=η_inh_EC*(f_EC)/[η_inh_EC*(f_EC)+η_inh_PDLLG*(f_PDLLG)]*100

vf_EC=0.746 dL/g*(0.0143)/[0.746 dL/g*(0.0143)+0.4dL/g*(0.9857)]*100=2.63%,  (Eq. 3)

which is reflected in Table 1 and calculated for subsequent Examples.

Lastly, monodisperse microspheres with 1% w/w ethyl cellulose andvarying drug concentrations were then fabricated in the manner describedpreviously. Drug content was determined by dissolving dried microspheresample (about 10 mg) in DCM and quantifying on a high performance liquidchromatography (HPLC) system outfitted with a C18 column. Actual drug,polymer, and ethyl cellulose contents are tabulated in Table 1. A smallsample was taken from the microsphere powder to obtain microscope imagesand size distribution with a Coulter Multisizer M3 (Samples 1.2, 1.4-1.5in FIGS. 1B, 1D and 1E, respectively). Samples 1.1 and 1.2 are EC-freecontrol samples and samples 1.3-1.5 each contain about 1% EC in theformulation.

TABLE 1 Sample ID 1.1 1.2 1.3 1.4 1.5 Polymer P-DLL-G P-DLL-G P-DLL-GP-DLL-G P-DLL-G Type Co-Block 65-35 65-35 65-35 65-35 65-35 Ratios (%-%)Polymer 0.40 0.40 0.40 0.40 0.40 Inherent Viscosity (dL/g) Absolute70.60 61.49 69.57 60.26 50.11 Polymer Content (% w/w) Relative 100.00100.00 98.57 98.33 98.00 Polymer Content in Matrix (%) EC Kinematic — —22 22 22 Viscosity (cP) EC Inherent — — 0.75 0.75 0.75 Viscosity (dL/g)Absolute EC — — 1.01 1.01 1.01 Content (% w/w) Relative EC — — 1.43 1.672.00 Content in Matrix (% w/w) EC Viscosity — — 2.63 3.07 3.67 Fraction(%) Drug A A A A A Absolute 29.40 38.51 29.42 38.73 48.88 Drug Content(% w/w) Toluene: 0.527 Ethanol 80:20 viscosity (cP)

FIGS. 1A to 1E shows plots of particle size distribution andphotomicrographs of microspheres of Samples 1.1 to 1.5, respectively.Data from Samples 1.3-1.5 demonstrate that inclusion of ethyl celluloseimproves microsphere droplet formation and decreases deviation in meanmicrosphere diameter compared to Samples 1.1 and 1.2 that do not includeethyl cellulose.

Example 2

Monodisperse microspheres with and without ethyl cellulose werefabricated as described in Example 1, only with P-DLL-G 85:15 and a 40%theoretical load of Drug B (Samples 2.1-2.2).

TABLE 2 Sample ID 2.1 2.2 Polymer Type P-DLL-G P-DLL-G Co-Block Ratios(%-%) 85-15 85-15 Polymer Inherent Viscosity (dL/g) 0.70 0.70 AbsolutePolymer Content (% w/w) 64.32 62.38 Relative Polymer Content in Matrix(%) 100.00 98.33 EC Kinematic Viscosity (cP) — 22 EC Inherent Viscosity(dL/g) — 0.75 Absolute EC Content (% w/w) — 1.04 Relative EC Content inMatrix (% w/w) — 1.67 EC Viscosity Fraction (%) — 1.77 Drug B B AbsoluteDrug Content (% w/w) 35.68 36.58

The photographs in FIG. 2 demonstrate that inclusion of ethyl celluloseimproves microsphere droplet formation, decreases deviation in meanmicrosphere diameter, and improved drug entrapment efficiency.Specifically, when ethylcellulose is included, microsphere sphericity ishighly predictable (Sample 2.2), whereas without ethylcellulose, someparticles are oblong, eccentric, or pill-shaped (Sample 2.1).Additionally, the diameter variation of microspheres withoutethylcellulose is much wider and inconsistent compared to particles withethylcellulose.

Example 3

Monodisperse microspheres with and without ethyl cellulose werefabricated as described in Example 1, only using P-DLL-G 75:25 and a 40%theoretical load of Drug B (Samples 3.1-3.2).

TABLE 3 Sample ID 3.1 3.2 Polymer Type P-DLL-G P-DLL-G Co-Block Ratios(%-%) 75-25 75-25 Polymer Inherent Viscosity (dL/g) 0.85 0.85 AbsolutePolymer Content (% w/w) 68.23 60.70 Relative Polymer Content in Matrix(%) 100.00 98.33 EC Kinematic Viscosity (cP) — 22 EC Inherent Viscosity(dL/g) — 0.75 Absolute EC Content (% w/w) — 1.02 Relative EC Content inMatrix (% w/w) — 1.67 EC Viscosity Fraction (%) — 1.47 Drug B B AbsoluteDrug Content (% w/w) 31.77 38.28

The photographs in FIG. 3 demonstrate that inclusion of ethyl celluloseimproves microsphere droplet formation, decreases deviation in meanmicrosphere diameter, and improved drug entrapment efficiency. Whenethylcellulose is included (Sample 3.2), microsphere sphericity ishighly predictable, whereas without ethylcellulose (Sample 3.1), someparticles are oblong, eccentric, or pill-shaped. Additionally, thediameter variation of microspheres without ethylcellulose is much widerand inconsistent compared to particles with ethylcellulose.

Example 4

Monodisperse microspheres with and without ethyl cellulose werefabricated as described in Example 1, only usingpoly(L-lactide-co-glycolide) (P-LL-G) 85:15 and varying concentrationsof Drug C (Samples 4.1-4.2). 4.1 is a drug-free and EC-free sample, 4.2and 4.3 are EC-free samples.

TABLE 4 Sample ID 4.1 4.2 4.3 4.4 4.5 Polymer Type P-LL-G P-LL-G P-LL-GP-LL-G P-LL-G Co-Block Ratios (%-%) 85-15 85-15 85-15 85-15 85-15Polymer Inherent 2.15 2.15 2.15 2.15 2.15 Viscosity (dL/g) AbsolutePolymer 100.00 71.86 67.96 70.32 59.59 Content (% w/w) Relative Polymer100.00 100.00 100.00 98.57 98.33 Content in Matrix (%) EC Kinematic — —— 22 22 Viscosity (cP) EC Inherent — — — 0.75 0.75 Viscosity (dL/g)Absolute EC — — — 1.01 1.01 Content (% w/w) Relative EC Content in — — —1.43 1.67 Matrix (% w/w) EC Viscosity — — — 0.50 0.58 Fraction (%) Drug— C C C C Absolute Drug — 28.14 32.04 28.67 39.40 Content (% w/w)

Data from Samples 4.4-4.5 demonstrate that inclusion of ethyl celluloseimproves microsphere droplet formation and decreases deviation in meanmicrosphere diameter compared to Samples 4.1, 4.2 and 4.3 that do notinclude ethyl cellulose.

Example 5

Monodisperse microspheres were fabricated as described in Example 1,only using poly(D,L-lactide) (P-DL-G) 100:0 or P-DLL-G 85:15, Drug C,and varying concentrations of ethyl cellulose (Samples 5.1-5.6).

TABLE 5 Sample ID 5.1 5.2 5.3 5.4 5.5 5.6 Polymer Type P-DLL P-DLL P-DLLP-DLL-G P-DLL-G P-DLL-G Co-Block Ratios (%-%) 100-0 100-0 100-0 85-1585-15 85-15 Polymer Inherent Viscosity (dL/g) 0.30 0.30 0.30 0.70 0.700.70 Absolute Polymer Content (% w/w) 81.59 81.51 78.33 81.33 79.8875.30 Relative Polymer Content in Matrix (%) 100.00 98.75 93.75 100.0098.75 93.75 EC Kinematic Viscosity (cP) — 22 22 — 22 22 EC InherentViscosity (dL/g) — 0.75 0.75 — 0.75 0.75 Absolute EC Content (% w/w) —1.03 5.18 — 1.01 5.02 Relative EC Content in Matrix (% w/w) — 1.25 6.25— 1.25 6.25 EC Viscosity Fraction (%) — 3.05 14.23 — 1.33 6.64 Drug C CC C C C Absolute Drug Content (% w/w) 18.41 17.46 16.49 18.67 19.1119.68

FIGS. 5A to 5F show plots of the cumulative release of the activeingredient from microspheres 5.1 to 5.6 respectively, as prepared inExample 5. Samples of each formulation type were stored for 0 weeks, 1week or 4 weeks at 40° C. (indicated as traces for each of the storageperiods). Samples were removed from the chamber after the storage periodand the dissolution was followed for seven days after removal fromstorage to provide the cumulative release plots indicated. The datarepresented in these Figures demonstrate that inclusion of ethylcellulose improved microsphere dissolution reproducibility after storagestability testing at 40° C./75% RH in sealed glass vials, but thebenefits of which are not present when the ethyl cellulose viscosityfraction is above 5%. Inclusion of ethyl cellulose also reduced therelease rate of the drug from the microspheres.

Example 6

Monodisperse microspheres were fabricated as described in Example 1,only using P-DLL 100:0, Drug C, and varying viscosities of ethylcellulose (Samples 6.1-6.3).

TABLE 6 Sample ID 6.1 6.2 6.3 Polymer Type P-DLL P-DLL P-DLL Co-BlockRatios (%-%) 100-0 100-0 100-0 Polymer Inherent Viscosity (dL/g) 0.300.30 0.30 Absolute Polymer Content (% w/w) 81.48 82.03 80.14 RelativePolymer Content in Matrix (%) 98.75 98.75 98.75 EC Kinematic Viscosity(cP) 4 22 100 EC Inherent Viscosity (dL/g) 0.41 0.75 1.05 Absolute ECContent (% w/w) 1.03 1.03 1.01 Relative EC Content in Matrix (% w/w)1.25 1.25 1.25 EC Viscosity Fraction (%) 1.68 3.05 4.24 Drug C C CAbsolute Drug Content (% w/w) 17.49 16.94 18.85

The data represented in FIG. 6 demonstrate that inclusion of ethylcellulose reduced the rate of drug release (compare sample 6.2 to sample5.1). The viscosity grade of the ethyl cellulose, related to molecularweight as discussed above, also affects release rate of Drug C.

Example 7

Monodisperse microspheres were fabricated as described in Example 1,only using a higher viscosity P-DLL 100:0, Drug C, and varyingviscosities of ethyl cellulose (Samples 7.1-7.3).

TABLE 7 Sample ID 7.1 7.2 7.3 Polymer Type P-DLL P-DLL P-DLL Co-BlockRatios (%-%) 100-0 100-0 100-0 Polymer Inherent Viscosity (dL/g) 1.501.50 1.50 Absolute Polymer Content (% w/w) 77.95 81.07 80.93 RelativePolymer Content in Matrix (%) 98.75 98.75 98.75 EC Kinematic Viscosity(cP) 4 22 100 EC Inherent Viscosity (dL/g) 0.41 0.75 1.05 Absolute ECContent (% w/w) 0.99 1.02 1.02 Relative EC Content in Matrix (% w/w)1.25 1.25 1.25 EC Viscosity Fraction (%) 0.34 0.63 0.88 Drug C C CAbsolute Drug Content (% w/w) 21.06 17.91 18.05

The data represented in FIG. 7 demonstrates that the viscosity of ethylcellulose affects release rate of Drug C.

Example 8

Monodisperse microspheres were fabricated as described in Example 1,only using P-DLL-G 85:15, Drug C, and varying viscosities of ethylcellulose (Samples 8.1-8.3).

TABLE 8 Sample ID 8.1 8.2 8.3 Polymer Type P-DLL-G P-DLL-G P-DLL-GCo-Block Ratios (%-%) 85-15 85-15 85-15 Polymer Inherent Viscosity(dL/g) 0.70 0.70 0.70 Absolute Polymer Content (% w/w) 78.56 79.43 80.30Relative Polymer Content in Matrix (%) 98.75 98.75 98.75 EC KinematicViscosity (cP) 4 22 100 EC Inherent Viscosity (dL/g) 0.41 0.75 1.05Absolute EC Content (% w/w) 1.00 1.00 1.01 Relative EC Content in Matrix(% w/w) 1.25 1.25 1.25 EC Viscosity Fraction (%) 0.73 1.33 1.86 Drug C CC Absolute Drug Content (% w/w) 20.44 19.57 18.69

The data represented in FIG. 8 demonstrates that the viscosity of ethylcellulose affects release rate of Drug C.

Example 9

Monodisperse microspheres were fabricated as described in Example 1,only using a higher viscosity P-DLL-G 85:15, Drug C, and varyingviscosities of ethyl cellulose (Samples 9.1-9.3).

TABLE 9 Sample ID 9.1 9.2 9.3 Polymer Type P-DLL-G P-DLL-G P-DLL-GCo-Block Ratios (%-%) 85-15 85-15 85-15 Polymer Inherent Viscosity(dL/g) 1.50 1.50 1.50 Absolute Polymer Content (% w/w) 78.39 79.64 81.27Relative Polymer Content in Matrix (%) 98.75 98.75 98.75 EC KinematicViscosity (cP) 4 22 100 EC Inherent Viscosity (dL/g) 0.41 0.75 1.05Absolute EC Content (% w/w) 0.99 1.01 1.02 Relative EC Content in Matrix(% w/w) 1.25 1.25 1.25 EC Viscosity Fraction (%) 0.34 0.63 0.88 Drug C CC Absolute Drug Content (% w/w) 20.62 19.35 17.71

The data represented in FIG. 9 demonstrates that the viscosity of ethylcellulose affects release rate of Drug C (FIG. 9 ).

Example 10

Monodisperse microspheres were fabricated as described in Example 1,only using P-LL-G 82:18, Drug C, and varying viscosities of ethylcellulose (Samples 10.1-10.3).

TABLE 10 Sample ID 10.1 10.2 10.3 Polymer Type P-LL-G P-LL-G P-LL-GCo-Block Ratios (%-%) 82-18 82-18 82-18 Polymer Inherent Viscosity(dL/g) 2.15 2.15 2.15 Absolute Polymer Content (% w/w) 81.30 81.18 80.30Relative Polymer Content in Matrix (%) 98.75 98.75 98.75 EC KinematicViscosity (cP) 4 22 100 EC Inherent Viscosity (dL/g) 0.41 0.75 1.05Absolute EC Content (% w/w) 1.02 1.02 1.01 Relative EC Content in Matrix(% w/w) 1.25 1.25 1.25 EC Viscosity Fraction (%) 0.24 0.44 0.61 Drug C CC Absolute Drug Content (% w/w) 17.68 17.80 18.69

The data represented in FIG. 10 demonstrate that the viscosity of ethylcellulose affects release rate of Drug C.

Example 11

Monodisperse microspheres were fabricated as described in Example 1,only using poly(L-lactide-co-D,L-lactide) 70:30, Drug C, and varyingviscosities of ethyl cellulose (Samples 11.1-11.3).

TABLE 11 Sample ID 11.1 11.2 11.3 Polymer Type P-LL-DLL P-LL-DLLP-LL-DLL Co-Block Ratios (%-%) 70-30 70-30 70-30 Polymer Inherent 2.402.40 2.40 Viscosity (dL/g) Absolute Polymer 80.25 82.54 79.46 Content (%w/w) Relative Polymer 98.75 98.75 98.75 Content in Matrix (%) ECKinematic Viscosity (cP) 4 22 100 EC Inherent Viscosity (dL/g) 0.41 0.751.05 Absolute EC Content (% w/w) 1.01 1.04 1.00 Relative EC Content 1.251.25 1.25 in Matrix (% w/w) EC Viscosity Fraction (%) 0.21 0.39 0.55Drug C C C Absolute Drug Content (% w/w) 18.74 16.42 19.54

The data represented in FIG. 11 demonstrates that the viscosity of ethylcellulose affects release rate of Drug C.

The results of Examples 6 to 11 show that the release rate of the drugis influenced by the viscosity grade of the ethyl cellulose and theviscosity fraction that it contributes to the polymer matrix. Generally,the higher the viscosity fraction vf_EC in the matrix, the slower therelease rate. Release rate is also affected by the percentage of drugcontained in the formulation, with higher drug content providing fasterrelease rates. As noted above, the glycolide content of the polymer mayalso impact the influence of the cellulose-derived material (CDM) onrelease rate. Other factors that may influence the release rates includeviscosity matching between the polymer and the CDM, and the physicalproperties (i.e. water solubility) of the drug itself. Thus, it may bepossible to prepare formulations with an appropriate polymer, cellulosematerial, and drug loading to provide a desired release profile for agiven drug.

Example 12

Monodisperse microspheres were fabricated as described in Example 1,only using varying viscosities of P-DLL-G 85:15, P-DLL 100:0,combinations of P-DLL-G and P-DLL, Drug C, and one viscosity of ethylcellulose (Samples 12.1-12.5).

TABLE 12 Sample ID 12.1 12.2 12.3 12.4 12.5 Polymer Type P-DLL-G P-DLL-GP-DLL-G P-DLL 10% P- DLL/ 90% P- DLL-G Co-Block 85-15 85-15 85-15 100-0100-0/ Ratios (%-%) 85:15 Polymer Inherent 0.70 0.70 1.50 1.50 1.50Viscosity (dL/g) Absolute Polymer 91.75 82.36 79.89 80.39 80.78 Content(% w/w) Relative Polymer 98.75 98.75 98.75 98.75 98.75 Content in Matrix(%) EC Kinematic 22 22 22 22 22 Viscosity (cP) EC Inherent 0.75 0.750.75 0.75 0.75 Viscosity (dL/g) Absolute EC 1.15 1.04 1.01 1.01 1.02Content (% w/w) Relative EC 1.25 1.25 1.25 1.25 1.25 Content in Matrix(% w/w) EC Viscosity 1.33 1.33 0.63 0.63 0.63 Fraction (%) Drug C C C CC Absolute Drug 7.10 16.60 19.10 18.60 18.20 Content (% w/w)

The data represented in FIGS. 12A to 12C demonstrate that inclusion ofethyl cellulose improves microsphere dissolution reproducibility afterstability testing at 40° C. and 75% RH in sealed glass vials for 0, 1month and 6 months, where no drug burst is present in any formulation.Formulations 12.1, 12.2 and 12.3 each exhibited release profiles showingrelatively steady release rates up to around 40 to 55 days, followed bymuch faster release rates until the cumulative release plateaued ataround 70 days. Without being bound by theory, the faster release ratemay be due to disruption of the physical integrity of the microspherescaused by hydrolytic degradation of the polymer and/or mechanicalerosion of the microspheres. Formulation 12.4, comprising a PLA ratherthan a PLGA as the major polymer had a similar, albeit slower releaseprofile, with the breakpoint between the slower and faster release ratesat about 110 days and the maximum release at about 155 days. Formulation12.5, comprising a small amount of PLA mixed with PLGA, showed a releaserate profile that is slightly extended compared to the samples withoutPLA. As in the previous examples, the release profile is also influencedby drug loading, having higher cumulative release with higher loading(compare 12.2 to 12.1).

Recommended storage conditions for PLA and PLGA-based formulations callfor storage at −20° C. Surprisingly, each of the formulations testedshow generally similar release profiles despite differing lengths ofstorage time at elevated temperatures, demonstrating good formulationstability even with extended storage at 40° C.

Example 13

Monodisperse microspheres were fabricated as described in Example 1,only using P-DLL-G 50:50, and Drug D with and without ethyl cellulose(Samples 13.1-13.2).

TABLE 13 Sample ID 13.1 13.2 Polymer Type P-DLL-G P-DLL-G Co-BlockRatios (%-%) 50-50 50-50 Polymer Inherent Viscosity (dL/g) 0.38 0.38Absolute Polymer Content (% w/w) 88.00 87.41 Relative Polymer Content inMatrix (%) 100.00 98.75 EC Kinematic Viscosity (cP) — 22 EC InherentViscosity (dL/g) — 0.75 Absolute EC Content (% w/w) — 1.09 Relative ECContent in Matrix (% w/w) — 1.25 EC Viscosity Fraction (%) 1 2.43 Drug DD Absolute Drug Content (% w/w) 12.00 11.50

The data represented in FIG. 13 demonstrates that inclusion of ethylcellulose improves microsphere size distribution of a very water solublepeptide.

Therefore, the present disclosure is well adapted to attain the ends andadvantages mentioned as well as those that are inherent therein. Theparticular embodiments disclosed above are illustrative only, as thepresent disclosure may be modified and practiced in different butequivalent manners apparent to those skilled in the art having thebenefit of the teachings herein. Features of the disclosed embodimentsmay be combined, rearranged, omitted, etc., within the scope of theinvention to produce additional embodiments. Furthermore, certainfeatures may sometimes be used to advantage without a corresponding useof other features. Furthermore, no limitations are intended to thedetails of construction or design herein shown, other than as describedin the claims below. It is therefore evident that the particularillustrative embodiments disclosed above may be altered or modified andall such variations are considered within the scope and spirit of thisinvention.

What is claimed is:
 1. A method for treating a subject having a diseaseor condition indicating a need for treatment comprising parenteraladministration, the method comprising administering to the subjectparentally a composition comprising a plurality of microspheres; whereineach microsphere comprises a polymer matrix and an active therapeuticagent; wherein the polymer matrix comprises a homogenous mixture of abiodegradable polymer and ethyl cellulose; wherein the biodegradablepolymer has a molecular weight of greater than 10,000 Daltons; andwherein the percentage of ethyl cellulose is from about 0.5% to about 6%w/w of each microsphere.
 2. The method of claim 1, wherein thepercentage of biodegradable polymer is from about 50% to about 95% w/wof each microsphere.
 3. The method of claim 1, wherein the percentage ofactive therapeutic agent is from about 10% to about 40% w/w of eachmicrosphere.
 4. The method of claim 1, wherein the biodegradable polymeris selected from the group consisting of a bulk-eroding polymer, asurface-eroding polymer, and a polyanhydride polymer.
 5. The method ofclaim 1, wherein the biodegradable polymer comprises a polyesterpolymer.
 6. The method of claim 5, wherein the polyester polymer ispoly(D,L-lactide), poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), orcombinations thereof.
 7. The method of claim 5, wherein the polyesterpolymer is a co-block polymer selected from the group consisting ofpoly(D,L-lactide-co-glycolide) and poly(L-lactide-co-glycolide).
 8. Themethod of claim 7, wherein the co-block polymer ispoly(D,L-lactide-co-glycolide) and wherein the percentage of lactide isfrom about 50% to about 80% w/w of the co-block polymer and wherein thepercentage of glycolide is from about 20% to about 50% w/w of theco-block polymer.
 9. The method of claim 7, wherein the co-block polymeris poly(L-lactide-co-glycolide) and wherein the percentage of lactide isfrom about 50% to about 80% w/w of the co-block polymer and wherein thepercentage of glycolide is from about 20% to about 50% w/w of theco-block polymer.
 10. The method of claim 1, wherein the biodegradablepolymer is a polylactide.
 11. The method of claim 10, wherein thepolylactide comprises: a racemic mixture of D-lactide and L-lactide,D-lactide enriched poly(D,L-lactide), L-lactide enrichedpoly(D,L-lactide), poly L-lactide, poly D-lactide, or a copolymercomprising blocks of L-lactide and D,L-lactide.
 12. The method of claim1, wherein a viscosity fraction of the ethyl cellulose in the polymermatrix is about 0.1% to about 5%.
 13. The method of claim 1, wherein theactive therapeutic agent is an integrase inhibitor, an antiparasitic, asteroid hormone, or a somatostatin analogue.
 14. The method of claim 1,wherein the active therapeutic agent is an organic compound having amolecular weight of less than 1000 daltons.
 15. The method of claim 1,further comprising a pharmaceutically acceptable carrier, excipient ordiluent.
 16. The method of claim 1, wherein the composition comprises anaqueous solution or a buffer solution.
 17. The method of claim 1,further comprising a pharmaceutical surfactant.
 18. The method of claim1, further comprising a cryoprotectant.
 19. The method of claim 1,wherein the composition releases the active therapeutic agent for atleast 7 days.
 20. The method of claim 1, wherein the compositionreleases the active therapeutic agent for at least about 40 days or forat least about 55 days.
 21. A method for treating a subject having adisease or condition indicating a need for treatment comprisingparenteral administration, the method comprising administering to thesubject parentally a composition comprising a plurality of microspheres;wherein each microsphere comprises a polymer matrix and an activetherapeutic agent; wherein the polymer matrix comprises a homogenousmixture of a biodegradable polyester polymer and a cellulose-derivedmaterial; wherein the biodegradable polyester polymer has a molecularweight of greater than 10,000 Daltons; wherein a viscosity fraction ofthe cellulose-derived material in the polymer matrix is about 0.1% toabout 5%; and wherein the percentage of the cellulose-derived materialis from about 0.5% to about 6% w/w of each microsphere.
 22. The methodof claim 21, wherein the biodegradable polyester polymer is apolylactide.
 23. The method of claim 22, wherein the polylactidecomprises: a racemic mixture of D-lactide and L-lactide, D-lactideenriched poly(D,L-lactide), L-lactide enriched poly(D,L-lactide), polyL-lactide, poly D-lactide, or a copolymer comprising blocks of L-lactideand D,L-lactide.
 24. The method of claim 21, wherein the biodegradablepolyester polymer is a co-block polymer selected from the groupconsisting of poly(D,L-lactide-co-glycolide) andpoly(L-lactide-co-glycolide).